Diazeniumdiolate cyclopentyl derivatives

ABSTRACT

A compound having the structure or a pharmaceutically acceptable salt thereof, wherein R 1  is hydrogen, —OH, —O—C 1-6  alkyl, ═O, or halogen; R 2  is hydrogen, C(O)OR 8 , C 6 H 5 C(O)OR 8 , (CH 2 ) 1-2 OH, CR 9 R 10 OH, C(O)O(CH 2 ) 0-2  aryl, C(O)NR 9 R 10 , C(O)SO 2 NR 9 R 10 , C 6 H 5 OR 9 , W—C(O)OR 8 , W—OR 9 , Y, or P(O)(OR 9 )(ORlO); R 3  is hydrogen or —C 1-6  alkyl; R 4  is hydrogen, —OH or —C(O)OR 9 ; R 5  is hydrogen or deuterium; R 6  and R 7  are independently —C 1-6  alkyl, fluoro-substituted —C 1-6  alkyl, deutero-substituted —C 1-6  alkyl or —(CH 2 ) 1-2 R 11 , wherein any carbon atom of the fluoro-substituted —C 1-6  alkyl is mono- or di-substituted with fluoro, and any carbon atom of the deutero-substituted —C 1-6  alkyl is mono- or di-substituted with fluoro; R 8 , in each instance in which it occurs, is independently hydrogen, —C 1-6  alkyl, or —(CH 2 ) 2 N + (CH 3 ) 3 ; R 9  and R 10 , in each instance in which they occur, are independently —C 1-6  alkyl; R 11  is —OH, —O—C 1-6  alkyl, -0CD3, —OC(O)OC 1-6  alkyl, —NH 2 , —C 6 H 5 , —N 3 , or W; W is an unsubslituted 5- or 6-raembered heteroaryl ring having 1, 2, or 3 nitrogen atoms, or a substituted 5- or 6-membered heteroaryl ring having 1, 2, or 3 nitrogen atoms that is mono- or di-substituted at any carbon atom with R 6  or R 7 ; Y is a 5- or 6-membered heterocyclic ring having 1, 2, 3 or 4 heteroatoms which are N, O, or S or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof, and methods of using the compounds for treating hypertension.

BACKGROUND OF THE INVENTION

WO09103875 describes diazeniumdiolate dihydro indole derivatives of aspecified formula for treating hypertension and cardiovascular disease.WO07144512 describes diazeniumdiolate tetrazole-biphenyl derivatives ofa specified formula for treating hypertension and cardiovasculardisease. US 2005137191 describes nitrate ester compounds, e.g.,1,2-dichloro-4-(2-methyl-butyldisulfanyl)-benzene, useful for preventingor mitigating tissue and/or cellular damage associated with aging,septic shock, ulcers, gastritis, ulcerative colitis and Crohn's disease.US 2005065194 describes use of an endothelial gene differentiationreceptor modulator such as1-(2-ethoxyphenyl)-3-(hydroxyphenylamino)-pyrrolidine-2,5-dione, tomodulate receptor-mediated biological activity such as cellproliferation stimulated by lysophosphatidic acid leading to ovariancancer and other forms of cancer, and to treat conditions such ascancer, cardiovascular disease, ischemia, and atherosclerosis. WO9746521 describes aliphatic nitrate esters useful for treatingneurological conditions, especially Parkinson's, Alzheimer's andHuntington's disease.

The present invention relates to novel diazeniumdiolate cycloalkanederivatives, useful as antihypertensive agents.

SUMMARY OF THE INVENTION

The present invention includes diazeniumdiolate cycloalkane derivatives,including various pharmaceutically acceptable salts and hydrates ofthese forms, and pharmaceutical formulations for controlled andsustained delivery of these forms to a patient.

The invention also includes a method for treating hypertension,Pulmonary Arterial Hypertension (PAH), congestive heart failure,conditions resulting from excessive water retention, cardiovasculardisease, diabetes, oxidative stress, endothelial dysfunction, cirrhosis,pre-eclampsia, osteoporosis or nephropathy, comprising administering acompounds of the invention to a patient having such a condition, orbeing at risk to having such condition.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

The invention is a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

-   R¹ is hydrogen, —OH, —O—C₁₋₆ alkyl, ═O, or halogen;-   R² is

hydrogen,

—C(O)OR⁸,

—C₆HSC(O)OR⁸,

—(CH₂)₁₋₂OH,

—CR⁹R¹⁰OH,

—C(O)O(CH₂)₀₋₂ aryl,

—C(O)NR⁹R⁰,

—C(O)SO₂NR⁹R¹⁰,

—C₆H₅OR⁹,

—W—C(O)OR⁸,

—W—OR⁹,

—Y, or

—P(O)(OR⁹)(OR¹⁰);

-   R³ is hydrogen or —C₁₋₆ alkyl;-   R⁴ is hydrogen, —OH, or —C(O)OR⁹;-   R⁵ is hydrogen or deuterium;-   R⁶ and R⁷ are independently —C₁₋₆ alkyl, fluoro-substituted-C₁₋₆    alkyl, deutero-substituted —C₁₋₆ alkyl or —(CH₂)₁₋₂R¹¹, wherein any    carbon atom of the fluoro-substituted-C₁₋₆ alkyl is mono- or    di-substituted with fluoro, and any carbon atom of the    deutero-substituted —C₁₋₆ alkyl is mono- or di-substituted with    fluoro;-   R⁸, in each instance in which it occurs, is independently hydrogen,    —C₁₋₆ alkyl, or —(CH₂)₂N⁺(CH₃)₃;-   R⁹ and R¹⁰, in each instance in which they occur, are independently    —C₁₋₆ alkyl;-   R¹¹ is —OH, —O—C₁₋₆ alkyl, —OCD3, —OC(O)OC₁₋₆ alkyl, —NH₂, —C₆H₅,    —N3, or W;-   W is an unsubstituted 5- or 6-membered heteroaryl ring having 1, 2,    or 3 nitrogen atoms, or a substituted 5- or 6-membered heteroaryl    ring having 1, 2, or 3 nitrogen atoms that is mono- or    di-substituted at any carbon atom with a group selected from R⁶ and    R⁷;-   Y is a 5- or 6-membered heterocyclic ring having 1, 2, 3 or 4    heteroatoms which are independently N, O or S,    and stereoisomers thereof, and pharmaceutically acceptable salts    thereof, and pharmaceutically acceptable salts of stereoisomers    thereof.

In one embodiment of the invention, the compound has the formula Ia:

In another embodiment of the invention, R¹ is hydrogen, —OH, —OCH₃, ═O,or F.

In another embodiment of the invention, R² is

—C(O)ORS,

—C₆H₅C(O)OR^(S),

—(CH₂)₁₋₂OH,

—C(O)O(CH₂)₀₋₂ aryl,

—C₆H₅OR⁹, or

—P(O)(OR⁹)(OR¹⁰).

In another embodiment of the invention, R² is

—C(O)OH,

—C(O)OCH₃,

—C(O)OCH₂CH₃,

—C(O)OC₆H₅,

—C(O)OCH₂CH₂N(CH₃)₃,

—C₆H₅C(O)OCH₂CH₃,

—C₆H₅C(O)OH,

—CH₂OH,

—C(O)OCH₂C₆H₅,

—C₆H₅OCH₃, or

—P(O)(OCH₂CH₃)₂.

In another embodiment of the invention, R³ is hydrogen or —CH₃.

In another embodiment of the invention, R³ is hydrogen.

In another embodiment of the invention, R⁴ is hydrogen, —OH, or—C(O)OCH₂CH₃.

In another embodiment of the invention, R⁴ is hydrogen.

In another embodiment of the invention, R⁵ is hydrogen.

In another embodiment of the invention, R⁶ is

—CH₃,

—CH(CH₃)₂,

—CH₂CH₃,

—(CH₂)₃CH₃,

—(CH₂)₂CH(CH₃)₂,

—(CH₂)₂OH,

—(CH₂)₂OCH₃,

—(CH₂)₂OCD₃,

—(CH₂)₂OC(O)OC(CH₃)₃,

—NH₂

—CH₂CH₂CH₃,

—CH₂CH₂N⁺ ₃, or

In another embodiment of the invention, R⁷ is —C(CH₃)₃ or —CH₂C₆H₅.

In another embodiment of the invention, R⁷ is —C(CH₃)₃.

In another embodiment of the invention, the compound is

-   (1R,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 1)-   ethyl    (1R,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate    (Ex. 1, step C)-   (1S,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 2)-   (1R,3R)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 3)-   (1S,3S)-3-({[(Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino)}oxy)cyclopentanecarboxylic    acid (Ex. 4)-   (1R,3R)-3-({[(1Z)-2-tert-butyl-2-(2-methoxyethyl)-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 5)-   2-{tert-butyl[(Z)-{[(1R,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]amino)}ethanol    (Ex. 5, step D)-   N-(2-methoxyethyl)-N—[(Z)-{[(1R,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methylpropan-2-amine    (Ex. 5, step E)-   (1R,3R)-3-({[(1Z)-2-tert-butyl-2-{2-[(²H₃)methyloxy]ethyl}-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 6)-   (1R,3R)-3-({[(1Z)-2-tert-butyl-2-propyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 7)-   (1R,3R)-3-({[(1Z)-2-tert-butyl-2-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 8)-   (1R,3R)-3-({[(1Z)-2-tert-butyl-2-(3-methylbutyl)-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 9)-   (1S,3R)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 10)-   (1S,3R)-3-({[(1Z)-2-tert-butyl-2-propyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid Ex. 11)-   (1S,3R)-3-({[(1Z)-2-tert-butyl-2-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 12)-   (1S,3R)-3-({[(1Z)-2-tert-butyl-2-(2-methoxyethyl)-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 13)-   (1S,3R)-3-({[(1Z)-2-{2-[(tert-butoxycarbonyl)oxy]ethyl}-2-tert-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 14)-   (1S,3R)-3-({[(1Z)-2-(2-aminoethyl)-2-tert-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 15)-   (1S,3R)-3-[({(1Z)-2-tert-butyl-1-oxido-2-[2-(1H-1,2,3-triazol-1-yl)ethyl]-1λ⁵-diazan-1-ylidene}amino)oxy]cyclopentanecarboxylic    acid (Ex. 16)-   (1R,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 17)-   (1S,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic    acid (Ex. 18)-   (1RS,3S,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-fluorocyclopentanecarboxylic    acid (Ex. 19)-   (1RS,3RS,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-methoxycyclopentanecarboxylic    acid (Ex. 20)-   (1RS,3RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-1-methylcyclopentanecarboxylic    acid (Ex. 21)-   (1RS,3SR)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-1-methylcyclopentanecarboxylic    acid (Ex. 22)    or pharmaceutically acceptable salts, thereof.

Compounds of the invention can be used to treat hypertension, treatangina, improve insulin sensitivity, and provide renal protection. Thecompounds can be used alone or in a fixed dose combination with otherantihypertensives such as, for example, angiotensin II receptorblockers, diuretics, ACE inhibitors, β-blockers, and calcium channelblockers.

Pharmaceutically acceptable salts include non-toxic salts such as thosederived from inorganic acids, e.g. hydrochloric, hydrobromoic, sulfuric,sulfamic, phosphoric, nitric and the like, or the quaternary ammoniumsalts which are formed, e.g., from inorganic or organic acids or bases.Examples of acid addition salts include acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, carbonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, lactobionate, laurylsulfate, malate,maleate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,nitrate, oleate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, stearate, succinate,sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Additionalspecific anionic salts include ascorbate, gluceptate, glutamate,glucoronate, besylate, caprylate, isetionate, gentisate, malonate,napasylate, edfisylate, pamoate, xinafoate, and napadisylate.

Base salts include ammonium salts, alkali metal salts such as sodium andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases such as dicyclohexylaminesalts, N-methyl-D-glucamine, and salts with amino acids such asarginine, lysine, and so forth. Also, the basic nitrogen-containinggroups may be quaternized with such agents as lower alkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides and others. Additional specific cationic saltsinclude tromethamine, benzathine, benethamine, diethylammonium,epolamine, hydrabamine.

When the compounds of the invention contain one chiral center, the term“stereoisomer” includes both enantiomers and mixtures of enantiomers,such as the specific 50:50 mixture referred to as the racemic mixture.The compounds of the present invention may have multiple chiral centers,providing for multiple stereoisomers. This invention includes all of thestereoisomers and mixtures thereof. Unless specifically mentionedotherwise, reference to one stereoisomer applies to any of the possiblestereoisomers. Whenever the stereoisomeric composition is unspecified,all possible stereoisomers are included. Where used, the structuremarking “*” indicates the location of a carbon atom that is a chiralcenter. When bonds to a chiral carbon are depicted as straight lines, itis understood that both (R) and (S) configurations of the chiral carbon,and hence both enantiomers and mixtures thereof, are represented.

Some of the compounds described herein may exist as tautomers. Theindividual tautomers as well as mixtures thereof are encompassed withthe described compounds.

As used herein except where noted, “alkyl” is intended to include bothbranched- and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. Commonly used abbreviationsfor alkyl groups are used throughout the specification, e.g. methyl maybe represented by conventional abbreviations including “Me” or CH₃ or asymbol that is an extended bond as the terminal group, e.g. “

”, ethyl may be represented by “Et” or CH₂CH₃, propyl may be representedby “Pr” or CH₂CH₂CH₃, butyl may be represented by “Bu” or CH₂CH₂CH₂ CH₃,etc. “C₁₋₄ alkyl” (or “C₁-C₄ alkyl”) for example, means linear orbranched chain alkyl groups, including all isomers, having the specifiednumber of carbon atoms. C₁₋₄ alkyl includes n-, iso-, sec- and t-butyl,n- and isopropyl, ethyl and methyl. If no number is specified, 1-4carbon atoms are intended for linear or branched alkyl groups.

Alkyl groups may be unsubstituted, or substituted with 1 to 3substituents on any one or more carbon atoms, with halogen, C₁-C₂₀alkyl, CF₃, NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NO₂, oxo, CN, N3,—OH, —O(C₁-C₆ alkyl), C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,(C₁-C₆ alkyl)S(O)₀₋₂—, HS(O)₀₋₂—, (C₁-C₆ alkyl)S(O)₀₋₂(C₁-C₆ alkyl)-,HS(O)₀₋₂(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)C(O)NH—, H₂N—C(NH)—, —O(C₁-C₆alkyl)CF₃, HC(O)—, (C₁-C₆ alkyl)C(O)—, HOC(O)—, (C₁-C₆ alkyl)OC(O)—,HO(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)O(C₁-C₆ alkyl)-, (C₁-C₆alkyl)C(O)₁₋₂(C₁-C₆ alkyl)-, HC(O)₁₋₂(C₁-C₆ alkyl)-, (C₁-C₆alkyl)C(O)₁₋₂—, HOC(O)NH—, (C₁-C₆ alkyl)OC(O)NH—, aryl, aralkyl,heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl,halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl,cyano-heterocycle and cyano-heterocyclylalkyl, where such substitutionresults in formation of a stable compound.

The term “aryl”, alone or in combination, relates to a phenyl, naphthylor indanyl group, preferably a phenyl group. The abbreviation “Ph”represents phenyl.

The term “heteroaryl” refers to an unsaturated ring having a specifiednumber of atom members (e.g., 5 or 6-membered), including a specifiednumber of heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms independentlyselected from N, O or S), e.g., 5-membered rings containing one nitrogen(pyrrole), one oxygen (pyran) or one sulfur (thiophene) atom, 5-memberedrings containing one nitrogen and one sulfur (thiazole) atom, 5-memberedrings containing one nitrogen and one oxygen (oxazole or isoxazole)atom, 5-membered rings containing two nitrogen (imidazole or pyrazole)atoms, five-membered aromatic rings containing three nitrogen atoms,five-membered aromatic rings containing one oxygen, one nitrogen or onesulfur atom, five-membered aromatic rings containing two heteroatomsindependently selected from oxygen, nitrogen and sulfur, 6-memberedrings containing one nitrogen (pyridine), or one oxygen (furan) atom,6-membered rings containing two nitrogen (pyrazine, pyrimidine, orpyridazine) atoms, 6-membered rings containing three nitrogen (triazine)atoms, a tetrazolyl ring; a thiazinyl ring; or coumarinyl. Examples ofsuch ring systems are furanyl, thienyl, pyrrolyl, pyridinyl,pyrimidinyl, indolyl, imidazolyl, triazinyl, thiazolyl, isothiazolyl,pyridazinyl, pyrazolyl, oxazolyl, and isoxazolyl.

The term “heterocyclic” refers to a saturated ring having a specifiednumber of atom members and a specified number of heteroatoms, in whichthe entire ring system (whether mono- or poly-cyclic) is saturated,e.g., a 4- to 8-membered saturated monocyclic ring or a stable 7- to12-membered bicyclic ring system which consists of carbon atoms and oneor more heteroatoms selected from N, O and S, a 5- or 6-memberedheterocyclic ring having 1 or 2 heteroatoms which are N, O or S, etc.Representative examples include piperidinyl, piperazinyl, azepanyl,pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl,isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl).

Aryl rings may be unsubstituted, or substituted with 1 substituent onany one or more carbon atoms, with halogen, C₁-C₂₀ alkyl, CF₃, NH₂,—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NO₂, oxo, CN, N3, —OH, —O(C₁-C₆alkyl), C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, HS(O)₀₋₂—,(C₁-C₆ alkyl)S(O)₀₋₂—, (C₁-C₆ alkyl)S(O)₀₋₂(C₁-C₆ alkyl)-,HS(O)₀₋₂(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)S(O)₀₋₂, (C₁-C₆ alkyl)C(O)NH—,HC(O)NH—, H₂N—C(NH)—, —O(C₁-C₆ alkyl)CF₃, (C₁-C₆ alkyl)C(O)—, HC(O)—,(C₁-C₆ alkyl)OC(O)—, HOC(O)—, (C₁-C₆ alkyl)O(C₁-C₆ alkyl)-, HO(C₁-C₆alkyl)-, (C₁-C₆ alkyl)C(O)₁₋₂(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)C(O)₁₋₂—,HC(O)₁₋₂(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)OC(O)NH—, HOC(O)NH—, aryl, aralkyl,heterocycle, heterocyclylalkyl, halo-aryl, halo-aralkyl,halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl, cyano-aralkyl,cyano-heterocycle and cyano-heterocyclylalkyl, where such substitutionresults in formation of a stable compound.

Heteroaryl and heterocyclic rings may be unsubstituted, or substitutedwith 1 substituent on any one or more carbon atoms, with halogen, C₁-C₂₀alkyl, CF₃, NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, NO₂, oxo, CN, N3,—OH, —O(C₁-C₆ alkyl), C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,(C₁-C₆ alkyl)S(O)₀₋₂—, HS(O)₀₋₂—, (C₁-C₆ alkyl)S(O)₀₋₂(C₁-C₆ alkyl)-,HS(O)₀₋₂(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)S(O)₀₋₂—, (C₁-C₆ alkyl)C(O)NH—,HC(O)NH—, H₂N—C(NH)—, —O(C₁-C₆ alkyl)CF₃, HC(O)—, (C₁-C₆ alkyl)C(O)—,(C₁-C₆ alkyl)OC(O)—, HOC(O)—, (C₁-C₆ alkyl)O(C₁-C₆ alkyl)-, HO(C₁-C₆alkyl)-, (C₁-C₆ alkyl)O—, (C₁-C₆ alkyl)C(O)₁₋₂(C₁-C₆ alkyl)-,HC(O)₁₋₂(C₁-C₆ alkyl)-, (C₁-C₆ alkyl)C(O)₁₋₂, (C₁-C₆ alkyl)OC(O)NH—,HOC(O)NH—, aryl, aralkyl, heterocycle, heterocyclylalkyl, halo-aryl,halo-aralkyl, halo-heterocycle, halo-heterocyclylalkyl, cyano-aryl,cyano-aralkyl, cyano-heterocycle or cyano-heterocyclylalkyl, orindependently or additionally substituted with 1 substituent on any oneor more nitrogen atoms, with C₁-C₂₀ alkyl, oxo, C₃-C₁₀ cycloalkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, aryl, —C(O)C₁₋₆ alkyl, —C(O)NHC₁-C₆ alkyl,—C(O)NH₂, —C₁-C₆ alkylC(O)NH₂, —C₁-C₆ alkylOC(O)NH₂, or independently oradditionally substituted with 1 substituent on any one or more sulfuratoms, with C₁-C₂₀ alkyl, oxo, C₃-C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, aryl, where such substitution results in formation of a stablecompound.

The compounds of the invention are useful for treating hypertension,Pulmonary Arterial Hypertension, congestive heart failure, angina,conditions resulting from excessive water retention, cardiovasculardiseases, diabetes, oxidative stress, endothelial dysfunction,cirrhosis, pre-eclampsia, osteoporosis, or nephropathy, comprisingadministering a compounds of the invention to a patient having such acondition, or being at risk to having such condition

The invention also relates to the use of compounds of the invention forthe preparation of a medicament for the treatment and/or prophylaxis ofthe above-mentioned diseases.

The above-mentioned compounds of the invention are also of use incombination with other pharmacologically active compounds comprisingangiotensin II receptor antagonists (e.g., losartan, valsartan,candesartan, irbesartan, olmesartan) angiotensin converting enzymeinhibitors (e.g, alacepril, benazepril, captopril, ceronapril,cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril,lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril,temocapril, or trandolapril), neutral endopeptidase inhibitors (e.g.,thiorphan and phosphoramidon), aldosterone antagonists, renin inhibitors(e.g. urea derivatives of di- and tri-peptides (See U.S. Pat. No.5,116,835), amino acids and derivatives (U.S. Pat. Nos. 5,095,119 and5,104,869), amino acid chains linked by non-peptidic bonds (U.S. Pat.No. 5,114,937), di- and tri-peptide derivatives (U.S. Pat. No.5,106,835), peptidyl amino diols (U.S. Pat. Nos. 5,063,208 and4,845,079) and peptidyl beta-aminoacyl aminodiol carbamates (U.S. Pat.No. 5,089,471); also, a variety of other peptide analogs as disclosed inthe following U.S. Pat. Nos. 5,071,837; 5,064,965; 5,063,207; 5,036,054;5,036,053; 5,034,512 and 4,894,437, and small molecule renin inhibitors(including diol sulfonamides and sulfinyls (U.S. Pat. No. 5,098,924),N-morpholino derivatives (U.S. Pat. No. 5,055,466), N-heterocyclicalcohols (U.S. Pat. No. 4,885,292) and pyrolimidazolones (U.S. Pat. No.5,075,451); also, pepstatin derivatives (U.S. Pat. No. 4,980,283) andfluoro- and chloro-derivatives of statone-containing peptides (U.S. Pat.No. 5,066,643), enalkrein, RO 42-5892, A 65317, CP 80794, ES1005, ES8891, SQ 34017, aliskiren((2S,4S,5S,7S)—N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamidhemifumarate) SPP600, SPP630 and SPP635), endothelin receptorsantagonists, vasodilators, calcium channel blockers (e.g., amlodipine,nifedipine, veraparmil, diltiazem, gallopamil, niludipine, nimodipins,nicardipine), potassium channel activators (e.g., nicorandil, pinacidil,cromakalim, minoxidil, aprilkalim, loprazolam), diuretics (e.g.,hydrochlorothiazide), sympatholitics, beta-adrenergic blocking drugs(e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, ormetoprolol tartate), alpha adrenergic blocking drugs (e.g., doxazocin,prazocin or alpha methyldopa) central alpha adrenergic agonists,peripheral vasodilators (e.g. hydralazine), lipid lowering agents (e.g.,simvastatin, lovastatin, ezetamibe, atorvastatin, pravastatin),metabolic altering agents including insulin sensitizing agents andrelated compounds (e.g., muraglitazar, glipizide, metformin,rosiglitazone) or with other drugs beneficial for the prevention or thetreatment of the above-mentioned diseases including nitroprusside anddiazoxide. Such combination can be achieved by combining two activeingredients in a single dosage formulation containing two independentactive ingredients, e.g., an angiotensin II receptor antagonist and anitrooxy cyclopentane derivative of the invention.

The dosage regimen utilizing the compound of the invention is selectedin accordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal andhepatic function of the patient; and the particular compound or saltthereof employed. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.

Oral dosages of the compounds of the invention, when used for theindicated effects, will range between about 0.0125 mg per kg of bodyweight per day (mg/kg/day) to about 7.5 mg/kg/day, preferably 0.0125mg/kg/day to 3.75 mg/kg/day, and more preferably 0.3125 mg/kg/day to1.875 mg/kg/day. For example, an 80 kg patient would receive betweenabout 1 mg/day and 600 mg/day, preferably 1 mg/day to 300 mg/day, morepreferably 25 mg/day to 150 mg/day, and more preferably 5 mg/day to 100mg/day. A suitably prepared medicament for once a day administrationwould thus contain between 1 mg and 600 mg, preferably between 1 mg and300 mg, and more preferably between 25 mg and 300 mg, e.g., 25 mg, 50mg, 100 mg, 150, 200, 250 and 300 mg. Advantageously, the compound ofthe invention may be administered in divided doses of two, three, orfour times daily. For administration twice a day, a suitably preparedmedicament would contain between 0.5 mg and 300 mg, preferably between0.5 mg and 150 mg, more preferably between 12.5 mg and 150 mg, e.g.,12.5 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg and 150 mg.

The compounds of the invention can be administered in such oral forms astablets, capsules and granules. The compounds of the invention aretypically administered as active ingredients in admixture with suitablepharmaceutical binders as described below. % w/w expresses the weightpercent of the indicated composition constituent compared to the totalcomposition. Suitable fillers used in these dosage forms includemicrocrystalline cellulose, silicified microcrystalline cellulose,dicalcium phosphate, lactose, mannitol, and starch, preferablymicrocrystalline cellulose, dicalcium phosphate, lactose or mixturesthereof. Suitable binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn-sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose, andpolyvinyl pyrrolidone. Lubricants used in these dosage forms includesodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride, sodium stearyl fumarate, stearic acidand the like, preferably magnesium stearate. Suitable coatingcompositions include aqueous dispersion or organic solution of insolublepolymers such as ethyl cellulose, cellulose aetate, cellulose acetatebutyrate and acrylate copolymers commercially known as Eudragit®.Plasticizers include triethyl citrate, dibutyl sebacate, dibutylphthalate, triacetin and castor oil. Antitacking agents include talc,kaolin, colloidal silica or mixtures thereof.

Methods of Synthesis

Several methods for preparing the compounds of this invention aredescribed in the following Schemes and Examples. Starting materials andintermediates are made from known procedures or as otherwiseillustrated.

Scheme 1 describes a convenient method to prepare the sodiumdiazeniumdiolates of the general structure 1-2 in this invention. Thesecondary amine 1-1 is treated with nitric oxide at an appropriatetemperature such as room temperature in the presence of a suitable basesuch as sodium hydroxide, sodium methoxide, or sodium tert-butoxide inan appropriate solvent such as acetonitrile, methanol, tetrahydrofuran,N,N-dimethylformamide, or water. Examples on the preparation of thesodium diazeniumdiolates can be found from the literature (Chakrapani,H.; Showalter, B. M.; Citro, M. L.; Keefer, L. K.; Saavedra, J. E. Org.Lett. 2007, 9, 4551-4554 and WO Patent 2009/094242.

Scheme 2 delineates a method to prepare O²-alkylated diazeniumdiolatesof the general structure 2-3 in this invention. Cyclopentanols of thegeneral structure 2-1 can be prepared from reduction of thecorresponding ketone, hydroboration/oxidation of the correspondingolefin, and ring opening of the corresponding epoxide. The alcohol 2-1can be activated for displacement at an appropriate temperature such asroom temperature with a suitable reagent such as methanesulfonicanhydride, benzenesulfonyl chloride, 4-(trifluoromethyl)phenylsulfonylchloride in the presence or absence of a base such asN,N-diisopropylethylamine, triethylamine, N-methylmorpholine, pyridine,or lutidine in an appropriate solvent such as dichloromethane,dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane,toluene, N,N-dimethylformamide, or N-methylpyrrolidinone. The resultantsulfonate 2-2 can be displaced by the appropriate sodiumdiazeniumdiolate salt 1-2 at an appropriate temperature such as roomtemperature in an appropriate solvent such as dichloromethane,dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane,toluene, N,N-dimethylformamide, or N-methylpyrrolidinone. Thestereochemistry at the sulfonate carbon is typically inverted as aresult of the displacement.

Scheme 3 describes a method to prepare O²-alkylated diazeniumdiolates ofthe general structure 3-5 in this invention. Organoboranes such asarylboronic acids, lithium trimethylarylborates, or potassiumaryltrifluoroborate can be added to cyclopentenone under the catalysisof a rhodium complex, such as bis(norbornadiene)rhodiumtetrafluoroborate, acetylacetonatobis(ethylene)rhodium(I), orchloro-(1,5-cyclooctadiene)rhodium(I)dimer, with an appropriate chiralligand, such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,2,2′-bis(diphenylphosphino)-6,6′-dimethoxy-1,1′-biphenyl, or2,5-dibenzylbicyclo[2.2.1]hepta-2,5-diene in an appropriate solvent suchas tetrahydrofuran, dioxane, or toluene with high enantioselectivity. Areview of some representative asymmetric catalytic systems capable ofachieving high enantioselectivity for the transformation can be found inHayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829-2844 and Shintani,R.; Hayashi, T. Aldrichimica Acta 2009, 2, 31-38. The ketone 3-1 can bereduced to the alcohol 3-2 either with conventional hydride donors suchas sodium borohydride or lithium aluminium hydride followed by enzymaticresolution, or in one-step with an enzymatic reducing system orstoichiometric or catalytic amount of organometallic reducing agentsthat can effect the reduction with high enantioselectivity. The alcohol3-2 can be activated for displacement at an appropriate temperature suchas room temperature with a suitable reagent such as methanesulfonicanhydride, benzenesulfonyl chloride, 4-(trifluoromethyl)phenylsulfonylchloride in the presence or absence of a base such asN,N-diisopropylethylamine, triethylamine, N-methylmorpholine, pyridine,or lutidine in an appropriate solvent such as dichloromethane,dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane,toluene, N,N-dimethylformamide, or N-methylpyrrolidinone. The resultantsulfonate 3-3 can be displaced by the appropriate sodiumdiazeniumdiolate salt 1-2 at an appropriate temperature such as roomtemperature in an appropriate solvent such as dichloromethane,dichloroethane, chloroform, acetonitrile, tetrahydrofuran, dioxane,toluene, N,N-dimethylformamide, or N-methylpyrrolidinone. Thestereochemistry at the sulfonate carbon is typically inverted as aresult of the displacement. Finally, the aryl group is oxidized to thecarboxylic acid with a catalytic amount of ruthenium salt, such asruthenium(III) chloride or ruthenium(IV) oxide, and a stoichiometricoxidant such as sodium periodate.

Scheme 4 describes a method to prepare functionalized O²-alkylateddiazeniumdiolates of the general structure 4-4 in this invention.cis-Diols 4-2 can be prepared from cis-dihydroxylation of olefins 4-1 bystoichiometric osmium tetroxide or catalytic osmium tetroxide with anappropriate stoichiometric oxidant such as 4-methylmorpholine N-oxide,sodium ferricyanate, or tert-butyl hydroperoxide. Cyclic sulfates 4-3can be prepared from these diols 4-2 with thionyl chloride followed byoxidation of the resultant cyclic sulfite with a catalytic rutheniumsalt such as ruthenium(III) chloride or ruthenium(IV) oxide with astoichiometric oxidant such as sodium periodate. These cyclic sulfates4-3 can be opened by the appropriate sodium diazeniumdiolate salt 1-2 atan appropriate temperature such as room temperature in an appropriatesolvent such as dichloromethane, dichloroethane, chloroform,acetonitrile, tetrahydrofuran, dioxane, toluene, N,N-dimethylformamide,or N-methylpyrrolidinone to afford 4-4. The hydroxyl group presentserves as a handle for further functionalization.

Abbreviations used in the examples below include DMAP(4-(N,N-dimethylamino)pyridine), DMF (N,N-dimethylformamide), NAD(nicotinamide adenine dinucleotide), DMSO (dimethyl sulfoxide), BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) TFA (trifluoroaceticacid), Ac (acetyl), SFC (Supercritical Fluid Chromatography), rt (roomtemperature), hr (hour), LC (liquid chromatography), THF(tetrahydrofuran), and TBAF (tetra-n-butylammonium fluoride).

Example 1

(1R,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid Step A: ethyl cis-3-hydroxycyclopentanecarboxylate

To a solution of ethyl 3-oxocyclopentanecarboxylate (10.0 g, 64.0 mmol)in 200 ml ethanol at 0° C. was added NaBH₄ (2.91 g, 77.0 mmol) inseveral portions. The mixture was stirred at 0° C. for 2 hr and then itwas concentrated. The residue was partitioned between ether (300 ml) andwater (300 ml). The organic layer was separated, washed with brine,dried over MgSO₄, and concentrated. The residue was purified by flashchromatography using 0 to 20% EtOAc/hexane gradient, affording the titlecompound.

Step B: ethylcis-3-({[4(trifluoromethyl)phenyl]sulfonyl}oxy)cyclopentanecarboxylate

To a solution of ethyl cis-3-hydroxycyclopentanecarboxylate (9.7 g, 61.3mmol) in 500 ml CH₂Cl₂ at 0° C. was added Et₃N (9.31 g, 92.0 mmol) andDMAP (0.75 g, 6.13 mmol), followed by 4-(trifluoromethyl)benzenesulfonylchloride (16.5 g, 67.4 mmol). After stirring at 0° C. for 1 hr and thenat rt for 1 hr, the mixture was concentrated and the residue waspartitioned between ether (300 ml) and water (300 ml). The organic layerwas washed with brine, dried over MgSO₄, and concentrated. The residuewas purified by flash chromatography on silica gel using 0 to 30%EtOAc/hexane gradient, affording the title compound: ¹H NMR (500 MHz,CDCl₃) δ 8.07 (d, J=8.2 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 5.07 (m, 1H),4.14 (m, 2H), 3.02 (m, 1H), 2.20-1.85 (m, 6H), 1.26 (m, 3H).

Step C: ethyl(1R,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate

To a solution of ethylcis-3-({[4(trifluoromethyl)phenyl]sulfonyl}oxy)cyclopentanecarboxylate(8.2 g, 22.4 mmol) in 100 ml DMF was added sodium1-(N-tert-butylethylamino)diazen-1-ium-1,2-diolate (4.92 g, 26.9 mmol).After stirring at 45° C. for 16 hr, the mixture was partitioned betweenether (300 ml) and water (300 ml). The organic layer was washed withbrine, dried over MgSO₄, and concentrated. The residue was purified byflash chromatography on silica gel using 0 to 30% EtOAc/hexane gradient,affording the title compound. ¹H NMR (500 MHz, CDCl₃) δ 4.02 (m, 1H),2.99 (m, 2H), 2.91 (m, 1H), 2.12-1.73 (m, 6H), 1.12 (m, 9H), 0.92 (m,3H). The enantiomeric mixture was separated by SFC with chiral IAcolumn, eluting with 10% 2:1:1 heptane:MeOH:EtOHICO₂, to give ethyl(1S,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylateas the fast elute compound and ethyl(1R,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylateas the slow elute compound. The absolute stereochemistry of theseenantiomers was assigned based on the products prepared according to theasymmetric synthetic procedure described in EXAMPLE 5.

Step D:(1R,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid

To a solution of(1R,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate(1.1 g, 3.65 mmol) (the slow eluting compound of Step C) in 10 mlethanol at rt was added 5N NaOH (2.0 ml, 10.0 mmol). After stirring atrt for 3 hr, the mixture was concentrated. The residue was partitionedbetween ether (30 ml) and 1N HCl (20 ml). The organic layer was washedwith brine, dried over MgSO₄, and concentrated to give the titlecompound: ¹H NMR (500 MHz, CDCl₃) δ 5.00 (m, 1H), 3.11 (m, 3H),2.30-1.90 (m, 6H), 1.25 (m, 9H), 1.05 (m, 3H).

Example 2

(1S,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid

To a solution of ethyl(1S,3S)-3-({[(Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate(0.78 g, 2.59 mmol) (the fast eluting compound, EXAMPLE 1 Step C) in 10ml ethanol at rt was added 5N NaOH (2.0 ml, 10.0 mmol). After stirringat rt for 3 hr, the mixture was concentrated. The residue waspartitioned between ether (30 ml) and 1N HCl (20 ml). The organic layerwas washed with brine, dried over MgSO₄, and concentrated to give thetitle compound: ¹H NMR (500 MHz, CDCl₃) δ 5.00 (m, 1H), 3.11 (m, 3H),2.30-1.90 (m, 6H), 1.25 (m, 9H), 1.05 (m, 3H).

Example 3 and 4(1R,3R)-3-({[(1Z-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid (Example 3) and(1S,3S)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid (Example 4)

The following examples were prepared using procedures analogous to thosedescribed for EXAMPLE 1 and 2 substituting sodium1-(N-tert-butylmethylamino)diazen-1-ium-1,2-diolate for sodium1-(N-tert-butylethylamino)diazen-1-ium-1,2-diolate in Step C.

EXAMPLE # t_(R) (min) LCMS 3 2.48 323.14[M + 23] 4 2.48 323.14[M + 23]

Example 5

(1R,3R)-3-({[(1Z)-2-tert-butyl-2-(2-methoxyethyl)-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid Step A: (3R)-3-(4-methoxyphenyl)cyclopentanone

To a solution of cyclopent-2-en-1-one (1.0 mL, 12.4 mmol),4-methoxyphenylboronic acid (3.76 g, 24.7 mmol), and (R)-BINAP (0.46 g,0.74 mmol) in a mixture of 1,4-dioxane (20 mL) and water (2 mL) at rtwas added ruthenium (0.19 g, 0.74 mmol). After stirring at 100° C.overnight, the mixture was cooled down to rt and partitioned betweenether (100 mL) and sat. NaHCO₃ (100 mL). The organic layer wasseparated, washed with sat. NaHCO₃ and brine, dried over MgSO₄, andconcentrated. The residue was purified by flash chromatography on silicagel using 0 to 30% EtOAc/hexane gradient, affording the title compound:¹H NMR δ 7.20 (d, J=8.6 Hz, 2H), 6.91 (d, J=8.7 Hz, 2H), 3.83 (s, 3H),3.40 (m, 1H), 2.66 (m, 1H), 2.46 (m, 2H), 2.33 (m, 2H), 1.97 (m, 1H).

Step B: (1S,3R)-3-(4-methoxyphenyl)cyclopentanol

To a 2 L 3-neck round bottom flask with thermocouple, heating mantle,and overhead stirrer was charged 47.41 g of starting(3R)-3-(4-methoxyphenyl)cyclopentanone was added 475 mL of 0.5M, pH=6.5phosphate buffer. To a solution of sodium formate (33.9 g) in 475 mL of0.5M, pH=6.5 phosphate buffer in a 1.0 L Erlenmeyer flask was addednicotinamide adenine dinucleotide (NAD) (975 mg), formate hydrogenase101 (1.95 g, Codexis) and ketoreductase NAD dependent 102 (975 mg,Biocatalytics). After adding the enzyme containing solution to thereaction flask, the reaction mixture was heated to 30° C. Afterovernight age, LC showed >98% conversion. Heating was discontinued andK₂CO₃ (285 g) was added to the reaction mixture. The mixture wastransferred to a separation funnel and was dilute with acetonitrile (950mL). The organic layer was separated and filtered through powderedcellulose. The residue was washed with acetonitrile (425 mL), which wasused to back extract the aqueous layer. The initial organic layer andthe back extraction were combined and concentrated to give the titlecompound: ¹H NMR δ 7.23 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.46(m, 1H), 3.82 (s, 3H), 3.03 (m, 1H), 2.49 (m, 1H), 2.07-1.80 (m, 5H),1.65 (m, 1H).

Step C: (1S,3R)-3-(4-methoxyphenyl)cyclopentyl4-(trifluoromethyl)benzenesulfonate

To a solution of (1S,3R)-3-(4-methoxyphenyl)cyclopentanol (1.19 g, 6.2mmol), triethylamine (0.86 mL, 6.2 mmol), and DMAP (0.76 g, 6.2 mmol) inCH₂Cl₂ (20 mL) at 0° C. was added 4-(trifluoromethyl)benzenesulfonylchloride (1.5 g, 6.2 mmol). After stirring at rt overnight, the mixturewas partitioned between Et₂O and sat. NaHCO₃. The organic layer wasseparated, washed with brine, dried over MgSO₄, and concentrated. Theresidue was purified by flash chromatography on silica gel using 0-30%EtOAc in hexanes to give the title compound: ¹H NMR (500 MHz, CDCl₃) δ8.08 (d, J=8.3 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 7.14 (d, J=8.6 Hz, 2H),6.85 (d, J=8.6 Hz, 2H), 5.15 (m, 1H), 3.81 (s, 3H), 3.00 (m, 1H), 2.50(m, 1H), 2.09-1.80 (m, 5H).

Step D:2-{tert-butyl[(Z)-{[(1R,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]amino}ethanol

To a solution of (1S,3R)-3-(4-methoxyphenyl)cyclopentyl4-(trifluoromethyl)benzenesulfonate (10.0 g, 24.97 mmol) in DMSO (100mL) was added sodium1-(N-tert-butyl-N-(2-hydroxyethyl)amino)diazen-1-ium-1,2-diolate (7.46g, 37.5 mmol). After stirring at rt for 16 hr, the mixture waspartitioned between Et₂O (300 ml) and water (300 ml), washed with brine,dried over MgSO₄, filtered and concentrated. The residue was purified byflash chromatography on silica gel using 0 to 30% EtOAc/hexane gradient,affording the title compound: ¹H NMR (500 MHz, CDCl₃) δ 7.16 (d, J=8.6Hz, 2H), 6.86 (d, J=8.6 Hz, 2H), 5.05 (m, 1H), 3.81 (s, 3H), 3.59 (m,2H), 3.34 (m, 1H), 3.28 (m, 2H), 2.36 (m, 3H), 2.25 (m, 1H), 2.02 (m,1H), 1.90 (m, 1H), 2.65 (m, 1H), 1.29 (s, 9H).

Step E:N-(2-methoxyethyl)-N—[(Z)-{[(1R,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methylpropan-2-amine

To a solution of2-{tert-butyl[(Z)-{[(1R,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]amino}ethanol(1 g, 2.85 mmol) in 10 ml DMF at 0° C. was added NaH (0.13 g, 3.56mmol), after 10 min, MeI (0.22 mL, 3.56 mmol) was added. The mixture wasgradually warmed up to rt and stirred over night. The reaction mixturewas partitioned between Et₂O (30 ml) and water (30 ml), washed withbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified by flash chromatography on silica gel using 0 to 30%EtOAc/hexane gradient, affording the title compound: ¹H NMR (500 MHz,CDCl₃) δ 7.13 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H), 5.05 (m, 1H),3.77 (s, 3H), 3.40 (m, 2H), 3.33 (s, 3H), 3.29 (m, 3H), 2.36 (m, 1H),2.30 (m, 1H), 2.20 (m, 1H), 2.00 (m, 1H), 1.85 (m, 1H), 1.60 (m, 1H),1.26 (s, 9H).

Step F:(1R,3R)-3-({[(1Z)-2-tert-butyl-2-(2-methoxyethyl)-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid

To a solution of sodium periodate (4.682 g, 21.89 mmol) in 12 ml waterwas added acetonitrile (8 ml), a solution ofN-(2-methoxyethyl)-N—[(Z)-{[(1R,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methylpropan-2-amine(400 mg, 1.094 mmol) in CCl₄ (8 ml), and followed by ruthenium (III)chloride hydrate (24.67 mg, 0.109 mmol). After stirring at rt for 30min, the reaction mixture was partitioned between Et₂O and 1N HCl. Theaqueous layer was separated and extracted with ether. The organic layerswere combined, dried over MgSO4, filtered and concentrated. The residuewas purified by flash chromatography on silica gel using 0-70% EtOAc inhexane to give the title compound as oil: ¹H NMR (500 MHz, CDCl₃) δ 4.92(m, 1H), 3.33 (m, 2H), 3.27 (s, 3H), 3.21 (m, 2H), 3.00 (m, 1H),2.22-1.83 (m, 6H), 1.17 (s, 9H).

Example 6

(1R,3R)-3-({[(1Z)-2-tert-butyl-2-{2-[(²H₃)methyloxy]ethyl}-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid

EXAMPLE 6 was prepared using the same procedure analogous to EXAMPLE 5substituting deuterated methyl iodide for methyl iodide in Step E: ¹HNMR (500 MHz, CDCl₃) δ 4.95 (m, 1H), 3.36 (m, 2H), 3.24 (m, 2H), 3.03(m, 1H), 2.25-1.83 (m, 6H), 1.20 (s, 9H).

Example 7-9

(1R,3R)-3-({[(1Z)-2-tert-butyl-2-propyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid (Example 7)(1R,3R)-3-({[(Z)-2-tert-butyl-2-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid (Example 8), and(1R,3R)-3-({[(1Z)-2-tert-butyl-2-(3-methylbutyl)-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid (Example 9)

The following examples were prepared using procedures analogous to thosedescribed for EXAMPLE 5 by substituting the appropriate sodium salt forsodium 1-(N-tert-butyl-N-(2-hydroxyethyl)amino)diazen-1-ium-1,2-diolate,DMF for DMSO, and reaction temperature 40-50° C. for rt in Step D.

EXAMPLE # R t_(R) (min) LCMS 7

3.26 310.16 [M + 23] 8

3.16 324.03 [M + 23] 9

3.29 338.15 [M + 23]

Example 10-12

(1S,3R)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid (Example 10),(1S,3R)-3-({[(1Z)-2-tert-butyl-2-propyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylic acid (Example 11), and(1S,3R)-3-({[(1Z)-2-tert-butyl-2-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid (Example 12)

The following examples were prepared using procedures analogous to thosedescribed for EXAMPLE 5 substituting (S)-BINAP for (R)-BINAP in Step Aand appropriate sodium salt for sodium1-(N-tert-butyl-N-(2-hydroxyethyl)amino)diazen-1-ium-1,2-diolate, DMFfor DMSO, and reaction temperature 40-50° C. for rt in Step D.

EXAMPLE # R t_(R) (min) LCMS 10

1.26 281.79 [M + 23] ¹H NMR (500 MHz, CDCl₃): δ 4.91-4.86 (m, 1H),2.93-2.87 (m, 1H), 2.80 (s, 3H), 2.45-2.25 (m, 2H), 2.26-2.10 (m, 2H),2.07-1.87 (m, 2H), 1.13 (s, 9H). 11

1.67 309.82 [M + 23] ¹H NMR (500 MHz, CDCl₃): δ 4.93-4.88 (m, 1H), 3.01(t, J = 7.4 Hz, 2H), 2.91-2.83 (m, 1H), 2.42- 2.33 (m, 1H), 2.31-2.24(m, 1H), 2.20-2.06 (m, 2H), 2.05-1.88 (m, 2H), 1.43-1.39 (m, 2H), 1.25(s, 9H), 0.95 (t, J = 7.4 Hz, 3H). 12

1.83 323.83 [M + 23] ¹HNMR (500 MHz, CDCl₃): δ 4.91-4.88 (m, 1H), 3.03(t, J = 6.5 Hz, 2H), 2.86 (q, J = 8.3 Hz, 1H), 2.42-2.32 (m, 1H),2.32-2.05 (m, 3H), 2.04-1.88 (m, 2H), 1.37 (m, 4H), 1.24 (s, 9H), 0.92(t, J = 6.6 Hz, 3H).

Example 13

(1S,3R)-3-({[(1Z)-2-tert-buty-2-(2-methoxyethyl)-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid

The title compound was prepared according to the procedures described inEXAMPLE 5 substituting (S)-BINAP for (R)-BINAP in Step A: ¹H NMR (500MHz, CDCl₃): δ 8.24 (bs, 1H), 4.96-4.92 (m, 1H), 3.43 (t, J=5.5 Hz, 2H),3.37 (s, 3H), 3.30 (t, J=5.4 Hz, 2H), 2.90 (q, J=8.1 Hz, 1H), 2.41-2.27(m, 2H), 2.24-1.82 (m, 4H), 1.26 (s, 9H).

Example 14

(1S,3R)-3-({[(1Z)-{2-{2-[(tert-butoxycarbonyl)oxy]ethyl}-2-tert-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid Step A: tert-butyl2-{tert-butyl[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]amino}ethylcarbonate

A solution of2-{tert-butyl[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]amino}ethanol(0.82 g, 2.33 mmol), prepared according to Example 5 step D substituting(S)-BINAP for (R)-BINAP in step A, di-tert-butyl dicarbonate (0.66 g,3.03 mmol), DMAP (0.057 g, 0.467 mmol), and triethylamine (0.425 g, 4.20mmol) were stirred under nitrogen in CH₂Cl₂ (5 mL). The reaction mixturewas stirred at rt overnight. The reaction mixture was partitionedbetween ethyl acetate and 10% aqueous citric acid. The organic layer waswashed with water and brine. The organic layer was dried over sodiumsulfate, filtered and evaporated. The crude was chromatographed onsilica gel, eluting with hexane-ethyl acetate (0-100%, 2 L), to affordthe title compound: ¹H NMR (500 MHz, CDCl₃): δ 7.24-7.13 (m, 2H), 6.87(d, J=8.3 Hz, 2H), 5.08-4.98 (m, 1H), 4.08 (t, J=5.8 Hz, 2H), 3.82 (s,3H), 3.48-3.33 (m, 2H), 3.09-2.99 (m, 1H), 2.65-2.55 (m, 1H), 2.19-2.12(m, 1H), 2.09-1.96 (m, 2H), 1.99-1.81 (m, 2H), 1.48 (s, 9H), 1.27 (s,9H).

Step B:(1S,3R)-3-({[(1Z)-2-{2-[(tert-butoxycarbonyl)oxy]ethyl}-2-tert-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid

The title compound was prepared according to the method described inEXAMPLE 5 Step F using tert-butyl2-{tert-butyl[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]amino}ethylcarbonate as the starting material: ¹H NMR (500 MHz, CDCl₃): δ 6.60-6.01(bs, 1H), 4.93-4.90 (m, 1H), 4.09-4.05 (m, 2H), 3.40 (t, J=5.9 Hz, 2H),2.89 (q, J=8.1 Hz, 1H), 2.37-2.26 (m, 2H), 2.26-2.07 (m, 3H), 2.08-1.86(m, 1H), 1.46 (s, 9H), 1.13 (s, 9H).

Example 15

(1S,3R)-3-({[(1Z)-2-(2-aminoethyl-2-tert-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid Step A:N-(2-azidoethyl)-N—[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methylpropan-2-amine

The title compound was prepared according to the method described inEXAMPLE 5 step D using2-{tert-butyl[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]amino}ethanol(3.6 g, 10.24 mmol) substituting (S)-BINAP for (R)-BINAP in step A, andreacting it with Zn(N₃)₂.2Py (4.7 g, 15.3 mmol), triphenylphosphine(5.37 g, 20.49 mmol), in anhydrous toluene diisopropyl azodicarboxylate(4.14 g, 20.49 mmol) in anhydrous toluene. The reaction mixture wasstirred until complete consumption of the alcohol. The mixture wasfiltered over a pad of diatomaceous earth, concentrated in vacuo andpurified by column chromatography eluting with hexane/ethyl acetate0-100%) to give the title compound: ¹H NMR (500 MHz, CDCl₃): δ 7.20 (d,J=8.3 Hz, 2H), 6.85 (d, J=8.3 Hz, 2H), 5.11-5.00 (m, 1H), 3.81 (s, 3H),3.35-3.25 (m, 41H), 3.11-3.01 (m, 1H), 2.61 (t, J=7.5 Hz, 1H), 2.20-2.19(m, 1H), 2.19-2.00 (m, 2H), 1.93-1.83 (m, 2H), 1.29 (s, 9H).

Step B:N-tert-butyl-N—[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]ethane-1,2-diamine

To a solution ofN-(2-azidoethyl)-N—[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methylpropan-2-amine(2.1 g, 5.58 mmol) in methanol was added Raney nickel (Sigma-Aldrich,Raney 2800 nickel, slurry in water, active catalyst). The mixture wasstirred at rt and the progress of the reaction was monitored by TLC.Upon completion, the reaction mixture was filtered through diatomaceousearth and the solvent was evaporated. The crude material was usedwithout purification.

Step C: tert-butyl(2-{tert-butyl[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]amino}ethyl)carbamate

To a solution ofN-tert-butyl-N—[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]ethane-1,2-diamine(1.38 g, 3.94 mmol), di-tert-butyl dicarbonate (1.17 g, 5.12 mmol) inmethylene chloride was added triethylamine (0.717 g, 7.09 mmol). Themixture was stirred at rt overnight. The reaction mixture waspartitioned between ethyl acetate and 10% aqueous citric acid. Theorganic layer was washed with water and brine. The organic layer wasdried over sodium sulfate, filtered and evaporated. The crude waschromatographed on silica gel, eluting with hexane-ethyl acetate(0-100%, 2 L), to afford the title compound: ¹H NMR (500 MHz, CDCl₃): δ7.29 (s, 1H), 7.19 (d, J=8.2 Hz, 2H), 6.87 (d, J=8.1 Hz, 2H), 4.99 (d,J=9.7 Hz, 1H), 3.81 (s, 3H), 3.23 (m, 2H), 3.14 (m, 2H), 3.11-3.00 (m,1H), 2.59 (t, J=14.1, 7.5 Hz, 1H), 2.17-1.83 (m, 5H), 1.46 (s, 9H), 1.26(s, 9H).

Step D:(1S,3R)-3-({[1)-2-(2-aminoethyl)-2-tert-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid

The title compound was prepared according to the method described inEXAMPLE 5 Step F using tert-butyl(2-{tert-butyl[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]amino}ethyl)carbamateas the starting material. The isolated compound was treated with TFA(100%) to give the title compound: ¹H NMR (500 MHz, CDCl₃): δ 9.31 (bs,2H), 7.60 (bs, 1H), 4.96 (m, 1H), 3.49-3.39 (m, 2H), 3.02-2.96 (m, 3H),2.49-2.45 (m, 1H), 2.01-1.91 (m, 5H), 1.24 (m, 9H).

Example 16

(1S,3R)-3-[({(1Z)-2-tert-butyl-1-oxido-2-[2-(1H-1,2,3-triazol-1-yl)ethyl]-1λ⁵-diazan-1-ylidene}amino)oxy]cyclopentanecarboxylicacid Step A:N—[(Z)-{[(1S,3R-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methyl-N-{2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]ethyl}propan-2-amine

A solution ofN-(2-azidoethyl)-N—[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methylpropan-2-amine(EXAMPLE 15 Step A, 1.00 g, 2.66 mmol) substituting (S)-BINAP for(R)-BINAP in step A and trimethylsilyl acetylene (0.522 g, 5.31 mmol) inanhydrous toluene was heated at 60° C. overnight. The solvent wasevaporated and the crude was chromatographed on silica gel eluting withhexane-ethyl acetate (0-100%, 2 L), to afford the title compound.

Step B:N—[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methyl-N-[2-(1H-1,2,3-triazol-1-yl)ethyl]propan-2-amine

To a solution ofN—[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methyl-N-{2-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]ethyl}propan-2-amine(0.960 g, 2.02 mmol) in THF (10 mL) was added TBAF (3.034 mL, 3.034mmol). The mixture was stirred at rt overnight. The solvent wasevaporated and the crude was chromatographed on silica gel eluting withhexane-ethyl acetate (0-100%, 2 L), to afford the title compound.

Step C:(1S,3R)-3-[({(1Z)-2-tert-butyl-1-oxido-2-[2-(H-1,2,3-triazol-1-yl)ethyl]-1λ⁵-diazan-1-ylidene}amino)oxy]cyclopentanecarboxylicacid

The title compound was prepared according to the method described inEXAMPLE 5 Step F usingN—[(Z)-{[(1S,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methyl-N-[2-(1H-1,2,3-triazol-1-yl)ethyl]propan-2-amineas the starting material: ¹H NMR (500 MHz, CDCl₃): δ 10.96 (bs, 1H),7.89 (s, 1H), 7.85 (s, 1H), 4.94 (s, 1H), 4.51-4.43 (m, 2H), 3.56-3.49(m, 2H), 3.01-2.87 (m, 1H), 2.43-2.20 (m, 2H), 2.23-1.91 (m, 4H), 1.13(s, 9H).

Example 17

(1R,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid Step A: benzyl cyclopent-3-ene-1-carboxylate

To a N,N-dimethylformamide solution (450 mL) of3-cyclopentene-1-carboxylic acid (50.0 g, 446 mmol) was added potassiumcarbonate (126 g, 913 mmol), followed by slow addition of benzyl bromide(80 mL, 669 mmol). After 3 hours, the reaction mixture was poured into500 mL water and extracted with diethyl ether (3×800 mL). The combinedorganic extracts were washed with brine, dried (magnesium sulfate), andconcentrated in vacuo to afford the title compound in a crude form. Itwas carried forward to the subsequent reaction without furtherpurification. ¹H NMR (500 MHz, CDCl₃) δ 7.43-7.29 (m, 5H), 5.68 (s, 2H),5.16 (s, 2H), 3.24-3.14 (m, 1H), 2.73-2.63 (m, 4H).

Step B: benzyl trans-3-hydroxycyclopentanecarboxylate

To a tetrahydrofuran solution (25 mL) of benzylcyclopent-3-ene-1-carboxylate (11.8 g, 43.3 mmol) in a 250-mLround-bottom flask under nitrogen at 0° C. was added 1.0 M boranetetrahydrofuran complex (22.0 mL, 22.0 mmol) over 15 minutes. The flaskwas removed from the ice bath and stirred for 2 hours. Water (50 mL) wasslowly added to the reaction mixture, followed by the slow addition ofsodium perborate tetrahydrate (6.66 g, 43.3 mmol) over 15 minutes. Themixture was stirred overnight 16 hr. Brine (50 mL) was added, and theorganic layer was removed. The aqueous white suspension was extractedwith ethyl acetate (3×100 mL), and the combined organic extracts werewashed with brine, dried (magnesium sulfate), and concentrated in vacuo.Chromatography over silica gel, eluting with hexanes/ethyl acetate,afforded the title compound as a colorless liquid. ¹H NMR (500 MHz,CDCl₃) δ 7.38-7.29 (m, 5H), 5.12 (s, 2H), 4.45 (d, J=4.6 Hz, 1H),3.16-3.06 (m, 1H), 2.17-1.80 (m, 5H), 1.68-1.61 (m, 1H).

Step C: benzyltrans-3-({[4(trifluoromethyl)phenyl]sulfonyl}oxy)cyclopentanecarboxylate

The title compound was made by following the procedures described inEXAMPLE 1, Step B substituting benzyltrans-3-hydroxycyclopentanecarboxylate for ethylcis-3-hydroxycyclopentanecarboxylate. ¹H NMR (500 MHz, CDCl₃) δ 8.03 (d,J=8.2 Hz, 2H), 7.82 (d, J=8.2 Hz, 2H), 7.38-7.29 (m, 5H), 5.15-5.08 (m,3H), 3.07 (qd, J=8.6, 6.2 Hz, 1H), 2.19-2.06 (m, 3H), 2.02-1.83 (m, 3H).

Step D: benzylcis-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate

The title compound was made by following the procedures described inEXAMPLE 1, Step C substituting benzyltrans-3-({[4(trifluoromethyl)phenyl]sulfonyl}oxy)cyclopentanecarboxylatefor ethylcis-3-({[4(trifluoromethyl)phenyl]sulfonyl}oxy)cyclopentanecarboxylate.¹H NMR (500 MHz, CDCl₃) δ 7.40-7.31 (m, 5H), 5.14 (s, 2H), 4.93-4.88 (m,1H), 3.11 (q, J=7.0 Hz, 2H), 2.87 (quintet, J=8.3 Hz, 1H), 2.41 (ddd,J=14.4, 8.9, 6.6 Hz, 1H), 2.26 (ddd, J=14.3, 8.5, 4.7 Hz, 1H), 2.16-2.05(m, 2H), 2.01-1.88 (m, 2H), 1.25 (s, 9H), 1.05 (t, J=7.0 Hz, 3H).Separation of the racemic mixture with Chiralpak AD-H column, elutingwith 4-40% isopropanol/carbon dioxide, afforded the (1R,3S)-enantiomeras the faster eluting product and the (1S,3R) as the slower elutingproduct.

Step E:(1R,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid

The title compound was made by following the procedures described inEXAMPLE 1, Step D substituting benzyl(1R,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylatefor ethyl(1S,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate.¹H NMR (500 MHz, CDCl₃) δ 4.93-4.87 (m, 1H), 3.10 (q, J=7.0 Hz, 2H),2.86 (quintet, J=8.3 Hz, 1H), 2.36 (ddd, J=14.5, 9.1, 6.3 Hz, 1H), 2.27(ddd, J=14.4, 7.9, 4.3 Hz, 1H), 2.17-2.06 (m, 2H), 2.03-1.87 (m, 2H),1.24 (s, 9H), 1.04 (t, J=7.0 Hz, 3H); LC-MS: m/z 296.2 (M+Na).

Example 18

(1S,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid

The title compound was made by following the procedures described inEXAMPLE 17, Step C substituting benzyl(1S,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylatefor benzyl(1R,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylatein step E.

Example 19

(1RS,3S,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-fluorocyclopentanecarboxylicacid Step A: methyl(3aR,5s,6aS)tetrahydro-3aH-cyclopenta[d][1,3,2]dioxathiole-5-carboxylate2,2-dioxide

To a dichloromethane (100 mL) solution of methyl3,4-dihydroxycyclopentanecarboxylate (14.7 g, 92.0 mmol) was addedthionyl chloride (8.05 mL, 110 mmol) slowly. After 2 hours, the reactionmixture was added to a stirring acetonitrile (100 mL)/water (100 mL)solution of sodium periodate (39.7 g, 185 mmol), followed byruthenium(IV) oxide hydrate (0.296 g, 1.96 mmol). After 3 hours, thereaction mixture was diluted with water (400 mL) and extracted withdiethyl ether (3×400 mL). The combined organic extracts were washed withbrine, dried (magnesium sulfate), and concentrated in vacuo to afford ablack solid. The residue was purified by column chromatography, elutingwith hexanes/ethyl acetate to give the title compound as the less polarfractions. ¹H NMR (500 MHz, CDCl₃) δ 5.38 (d, J=4.7 Hz, 2H), 3.73 (s,3H), 3.35 (tt, J=11.2, 6.5 Hz, 1H), 2.49 (dd, J=15.3, 6.6 Hz, 2H),2.19-2.11 (m, 2H).

Step B: methyl(1RS,3RS,4RS)-3-({[(1Z-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-hydroxycyclopentanecarboxylate

A mixture of methyl(3aR,5s,6aS)tetrahydro-3aH-cyclopenta[d][1,3,2]dioxathiole-5-carboxylate2,2-dioxide (0.821 g, 3.69 mmol) and sodium1-(N-tert-butylmethylamino)diazen-1-ium-1,2-diolate (0.812 g, 4.80 mmol)in tetrahydrofuran (15 mL) was heated at 60° C. for 16 hours. Once thereaction solution was cooled to room temperature, 4N aqueoushydrochloric acid in methanol (1.0 mL, 4.0 mmol) was added to thesolution and heated at 40° C. for 30 minutes. The solution was dilutedwith water and extracted with ethyl acetate (3×50 mL). The organics werewashed with brine, dried over magnesium sulfate, and concentrated invacuo. The residue was purified using column chromatography, affordingthe title compound as a colorless liquid: ¹H NMR (500 MHz, CDCl₃) δ4.63-4.59 (m, 1H), 4.45-4.42 (m, 1H), 3.69 (s, 3H), 3.09 (quintet, J=8.7Hz, 1H), 2.80 (s, 3H), 2.56-2.49 (m, 1H), 2.32-2.26 (m, 1H), 2.16-2.11(m, 1H), 2.00-1.93 (m, 1H), 1.23 (s, 9H).

Step C: methyl(1RS,3S,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-fluorocyclopentanecarboxylate

To a dichloromethane solution (20 mL) of methyl(1RS,3RS,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-hydroxycyclopentanecarboxylate (0.882 g, 3.05 mmol) at −78° C. was addedbis(2-methoxyethyl)aminosulfur trifluoride (1.5 mL, 3.62 mmol) over 2minutes. The reaction was stirred at −78° C. for 1 hour and then warmedto −20° C. in a methanol-ice bath. This reaction mixture was thenallowed to warm to room temperature over 6 hours and quenched withwater. It was extracted with ethyl acetate (3×70 mL), and the combinedorganic extracts were washed with saturated sodium bicarbonate, brine,and dried over magnesium sulfate. The organics were concentrated invacuo and purified by column chromatography (ethyl acetate/hexanes),affording the title compound as a colorless liquid. ¹H NMR (500 MHz,CDCl₃) δ 5.06 (dddd, J=53.6, 4.7, 3.6, 2.5 Hz, 1H), 4.60 (dtd, J=19.7,8.7, 3.6 Hz, 1H), 3.72 (s, 3H), 2.88 (qd, J=9.6, 6.1 Hz, 1H), 2.82 (s,3H), 2.49-2.38 (m, 3H), 2.23 (dddd, J=32.7, 15.4, 10.5, 4.8 Hz, 1H),1.24 (s, 9H).

Step D:(1RS,3S,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-fluorocyclopentanecarboxylicacid

The title compound was made by following the procedures described inEXAMPLE 1, Step D substituting methyl(1RS,3S,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-fluorocyclopentanecarboxylatefor ethyl(1S,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate. ¹H NMR (500 MHz, CDCl₃) δ 5.07 (ddt, J=53.4, 4.7, 3.1 Hz,1H), 4.63 (dtd, J=19.0, 8.4, 3.4 Hz, 1H), 2.93 (qd, J=9.4, 5.6 Hz, 1H),2.81 (s, 3H), 2.58-2.38 (m, 3H), 2.37-2.21 (m, 1H), 1.23 (s, 9H); LC-MS:m/z 299.9 (M+Na).

Example 20

(1RS,3RS,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-methoxycyclopentanecarboxylicacid Step A: methyl(1RS,3RS,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-methoxycyclopentanecarboxylate

To a chloroform (10 mL) solution of methyl(1RS,3RS,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxidohydrazono]amino}oxy)-4-hydroxycyclopentanecarboxylate(EXAMPLE 19, Step B, 451 mg, 1.56 mmol) was added1,8-bis(dimethylamino)naphthalene (717 mg, 3.34 mmol), followed bytrimethyloxonium tetrafluoroborate (478 mg, 3.23 mmol). After 64 hours,the reaction mixture was concentrated in vacuo, and the residue waspurified by column chromatography, eluting with hexanes/ethyl acetate togive the title compound as a yellow liquid. ¹H NMR (500 MHz, CDCl₃) δ4.71 (ddd, J=6.8, 5.2, 2.2 Hz, 1H), 3.94 (dt, J=6.0, 2.4 Hz, 1H); 3.68(s, 3H), 3.35 (s, 3H), 3.00 (quintet, J=8.7 Hz, 1H), 2.81 (s, 3H), 2.47(dt, J=14.4, 7.7 Hz, 1H), 2.24-2.10 (m, 2H), 2.04 (ddd, J=13.9, 7.8, 2.4Hz, 1H), 1.24 (s, 9H).

Step B:(1RS,3RS,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-methoxycyclopentanecarboxylicacid

The title compound was made by following the procedures described instep D, EXAMPLE 1 substituting methyl(1RS,3RS,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-methoxycyclopentanecarboxylatefor ethyl(1S,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate.¹H NMR (500 MHz, CDCl₃) δ 4.73 (td, J=5.7, 1.9 Hz, 1H), 3.97-3.93 (m,1H), 3.36 (s, 3H), 3.04 (quintet, J=8.7 Hz, 1H), 2.80 (s, 3H), 2.54-2.44(m, 1H), 2.24-2.13 (m, 2H), 2.10-2.05 (m, 1H), 1.23 (s, 9H); LC-MS: m/z312.2 (M+Na).

Example 21

(1RS,3RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-1-methylcyclopentanecarboxylicacid Step A: methyl(1RS,3RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-1-methylcyclopentanecarboxylate

Methyl iodide (0.40 mL, 6.4 mmol) was added to a tetrahydrofuransolution (20 mL) of lithium diisopropylamide (1.50 mL, 3.00 mmol) andmethyl(1R,3S)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate(0.525 g, 1.92 mmol) at −78° C. The solution was gradually warmed toroom temperature over 16 hours. It was then quenched with 1Nhydrochloric acid and extracted with ethyl acetate (3×30 mL). Theorganics were concentrated in vacuo and purified by columnchromatography (hexanes/ethyl acetate), affording the (1RS,3RS)diastereomer of the title compound as the less polar fractions and the(1RS,3SR) diastereomer as the more polar fractions. (1RS,3RS)diastereomer: ¹H NMR (500 MHz, CDCl₃) δ 4.94 (dt, J=11.0, 4.2 Hz, 1H),3.68 (s, 3H), 2.81 (s, 3H), 2.63 (dd, J=14.6, 6.8 Hz, 1H), 2.18-2.09 (m,1H), 2.08-2.01 (m, 2H), 1.82 (dd, J=14.6, 3.8 Hz, 1H), 1.76 (dt, J=12.8,8.6 Hz, 1H), 1.37 (s, 3H), 1.24 (s, 9H). (1RS,3SR) diastereomer: ¹H NMR(500 MHz, CDCl₃) δ 4.94-4.83 (m, 1H), 3.68 (s, 3H), 2.80 (s, 3H), 2.54(dd, J=14.4, 3.9 Hz, 1H), 2.41 (dt, J=13.1, 8.1 Hz, 1H), 2.18-2.01 (m,2H), 1.92 (dd, J=14.4, 6.4 Hz, 1H), 1.53 (ddd, J=13.1, 8.3, 5.8 Hz, 1H),1.24 (s, 9H).

Step B:(1RS,3RS)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy-1-methylcyclopentanecarboxylicacid

The title compound was made by following the procedures described instep D, EXAMPLE 1 substituting methyl(1RS,3RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-1-methylcyclopentanecarboxylatefor ethyl(1S,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate.¹H NMR (500 MHz, CDCl₃) δ 4.98-4.92 (m, 1H), 2.81 (s, 3H), 2.65 (dd,J=14.7, 6.7 Hz, 1H), 2.19 (ddd, J=12.8, 7.1, 5.3 Hz, 1H), 2.11-2.05 (m,2H), 1.85 (dd, J=14.6, 3.7 Hz, 1H), 1.80 (dt, J=12.9, 8.7 Hz, 1H), 1.40(s, 3H), 1.23 (s, 9H); LC-MS: m/z 274.3 (M+H).

Example 22

(1RS,3SR)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-1-methylcyclopentanecarboxylicacid

The title compound was made by following the procedures described inEXAMPLE 21 substituting methyl(1RS,3SR)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-1-methylcyclopentanecarboxylatefor methyl(1RS,3RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-1-methylcyclopentanecarboxylate in step B. ¹H NMR (500 MHz, CDCl₃) δ 4.94-4.89 (m, 1H), 2.80(s, 3H), 2.59 (dd, J=14.6, 3.2 Hz, 1H), 2.45 (dt, J=13.2, 8.1 Hz, 1H),2.15-2.05 (m, 2H), 1.90 (dd, J=14.6, 6.1 Hz, 1H), 1.56 (ddd, J=13.3,8.3, 5.9 Hz, 1H), 1.33 (s, 3H), 1.22 (s, 9H); LC-MS: m/z 274.3 (M+H).

Tables 1-5 describe additional examples of compounds within the scope ofthe invention:

TABLE 1

Ex R^(a) R² 23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

TABLE 2

Ex R^(a) R¹ R² 58

59

60

61

62

TABLE 3

Ex R^(a) R⁴ 63

64

TABLE 4

Ex R^(a) R² R³ 65

66

67

68

69

70

71

TABLE 5

Ex R^(a) R² R⁵ 72

73

Compounds of the invention were evaluated for blood pressure reductionefficacy using the following canine telemetry protocol described below.

Male beagle dogs (approximately 1-3 years old) with a body weight ofbetween 10 and 16 kg were surgically implanted with DSI radiotelemetrydevices (model: TL11M2-D70-PCT). Briefly, under an inhalant anesthesia,isoflurane/oxygen mixture (1-3.5%/to effect), the body of the telemetrydevice was positioned and secured intra-abdominally. Subsequently, thearterial catheter of the telemetry device was passed subcutaneously tothe inguinal area and introduced into the femoral artery and advanced tothe level of the descending aorta. The catheter was secured with 2-0silk ligatures. The muscle and underlying fascia was closed over thecatheter using absorbable suture and the skin was closed usingnon-absorbable suture. The animals were allowed a minimum recoveryperiod of 2 weeks between surgery and the evaluation of test compounds.

Compound evaluation consisted of a 3 day paradigm at a 3 mg/kg dose. Onthe first day, no compounds were administered during a 24 hour period ofbaseline data collection. Blood pressure and heart rate data werecollected continuously for one minute periods at 10 minute intervals. Onthe days of compound administration half the animals received testarticle with the other half receiving the vehicle used for compoundformulation. All test materials were administered by oral gavage in avolume of 1 mL/kg. Data are expressed either as raw values (mm Hg orbeats per minute) or as the change from baseline (average value forabout 12 hours in low activity period prior to dosing). Change is SBP(systolic blood pressure) and PP (pulse pressure) over time is shownbelow:

ΔSBP (mm Hg) ΔPP (mm Hg) Example 1-6 h 6-12 h 12-18 h 1-6 h 6-12 h 12-18h 1 −12 −9 −7 −7 −7 −5 7 −9 −11 −10 −4 −9 −8 18 −18 −10 −4 −14 −10 −6

1-18. (canceled)
 19. A compound having the formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen,—OH, —O—C₁₋₆ alkyl, ═O, or halogen; R² is hydrogen, —C(O)OR⁸,—C₆H₅C(O)ORS, —(CH₂)₁₋₂OH, —CR⁹R¹⁰OH, —C(O)O(CH₂)₀₋₂ aryl, —C(O)NR⁹R¹⁰,—C(O)SO₂NR⁹R¹⁰, —C₆H₅OR⁹, —W—C(O)OR⁸, —W—OR⁹, —Y, or —P(O)(OR⁹)(OR¹⁰);R³ is hydrogen or —C₁₋₆ alkyl; R⁴ is hydrogen, —OH, or —C(O)OR⁹; R⁵ ishydrogen or deuterium; R⁶ and R⁷ are independently —C₁₋₆ alkyl,fluoro-substituted-C₁₋₆ alkyl, deutero-substituted C₁₋₆ alkyl or—(CH₂)₁₋₂R¹¹, wherein any carbon atom of the fluoro-substituted-C₁₋₆alkyl is mono- or di-substituted with fluoro, and any carbon atom of thedeutero-substituted —C₁₋₆ alkyl is mono- or di-substituted with fluoro;R⁸, in each instance in which it occurs, hydrogen, —C₁₋₆ alkyl, or—(CH₂)₂N⁺(CH₃)₃; R⁹ and R¹⁰, in each instance in which they occur, areindependently —C₁₋₆ alkyl; R¹¹ is —OH, —O—C₁₋₆ alkyl, —OCD3, —OC(O)OC₁₋₆alkyl, —NH₂, —C₆H₅, —N3, or W; W is an unsubstituted 5- or 6-memberedheteroaryl ring having 1, 2, or 3 nitrogen atoms, or a substituted 5- or6-membered heteroaryl ring having 1, 2, or 3 nitrogen atoms that ismono- or di-substituted at any carbon atom with R⁶ or R⁷; Y is a 5- or6-membered heterocyclic ring having 1, 2, 3 or 4 heteroatoms which areN, O or S, or stereoisomers thereof, or pharmaceutically acceptablesalts thereof, or pharmaceutically acceptable salts of stereoisomersthereof.
 20. A compound of claim 19, wherein the compound has theformula Ia:

or a pharmaceutically acceptable salt thereof.
 21. A compound of claim19, wherein R¹ is hydrogen, —OH, —OCH₃, ═O, or F, or a pharmaceuticallyacceptable salt thereof.
 22. A compound of claim 19, wherein R² is—C(O)ORS, —C₆H₅C(O)OR⁸, —(CH₂)₁₋₂OH, —C(O)O(CH₂)₀₋₂ aryl, —C₆H₅OR⁹, or—P(O)(OR⁹)(OR¹⁰), or a pharmaceutically acceptable salt thereof.
 23. Acompound of claim 22, wherein R² is —C(O)OH, —C(O)OCH₃, —C(O)OCH₂CH₃,—C(O)OC₆H₅, —C(O)OCH₂CH₂N(CH₃)₃, —C₆H₅C(O)OCH₂CH₃, —C₆H₅C(O)OH, —CH₂OH,—C(O)OCH₂C₆H₅, —C₆H₅OCH₃, or —P(O)(OCH₂CH₃)₂ or a pharmaceuticallyacceptable salt thereof.
 24. A compound of claim 22, wherein R³ ishydrogen or —CH₃, or a pharmaceutically acceptable salt thereof.
 25. Acompound of claim 24, wherein R³ is hydrogen, or a pharmaceuticallyacceptable salt thereof.
 26. A compound of claim 25, wherein R⁴ ishydrogen, —OH, or —C(O)OCH₂CH₃, or a pharmaceutically acceptable saltthereof.
 27. A compound of claim 26, wherein R⁴ is hydrogen, or apharmaceutically acceptable salt thereof.
 28. A compound of claim 19,wherein R⁵ is hydrogen, or a pharmaceutically acceptable salt thereof.29. A compound of claim 19, wherein R⁶ is —CH₃, —CH(CH₃)₂, —CH₂CH₃,—(CH₂)₃CH₃, —(CH₂)₂CH(CH₃)₂, —(CH₂)₂OH, —(CH₂)₂OCH₃, (CH₂)₂OCD₃,—(CH₂)₂OC(O)OC(CH₃)₃, —NH₂ —CH₂CH₂CH₃, —CH₂CH₂N⁺ ₃, or

or a pharmaceutically acceptable salt thereof.
 30. A compound of claim19, wherein R⁷ is —C(CH₃)₃ or —CH₂C₆H₅, or a pharmaceutically acceptablesalt thereof.
 31. A compound of claim 30, wherein R⁷ is —C(CH₃)₃, or apharmaceutically acceptable salt thereof.
 32. A compound of claim 19,which is(1R,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid, ethyl(1R,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ5-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylate,(1S,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1R,3R)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1S,3S)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1R,3R)-3-({[(1Z)-2-tert-butyl-2-(2-methoxyethyl)-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,2-{tert-butyl[(Z)-{[(1R,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]amino}ethanol,N-(2-methoxyethyl)-N—[(Z)-{[(1R,3R)-3-(4-methoxyphenyl)cyclopentyl]oxy}-NNO-azoxy]-2-methylpropan-2-amine,(1R,3R)-3-({[(1Z)-2-tert-butyl-2-{2-[(²H₃)methyloxy]ethyl}-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1R,3R)-3-({[(1Z)-2-tert-butyl-2-propyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1R,3R)-3-({[(1Z)-2-tert-butyl-2-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1R,3R)-3-({[(1Z)-2-tert-butyl-2-(3-methylbutyl)-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1S,3R)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1S,3R)-3-({[(1Z)-2-tert-butyl-2-propyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1S,3R)-3-({[(1Z)-2-tert-butyl-2-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1S,3R)-3-({[(1Z)-2-tert-butyl-2-(2-methoxyethyl)-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1S,3R)-3-({[(1Z)-2-{2-[(tert-butoxycarbonyl)oxy]ethyl}-2-tert-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1S,3R)-3-({[(1Z)-2-(2-aminoethyl)-2-tert-butyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1S,3R)-3-[({(1Z)-2-tert-butyl-1-oxido-2-[2-(1H-1,2,3-triazol-1-yl)ethyl]-1λ⁵-diazan-1-ylidene}amino)oxy]cyclopentanecarboxylicacid,(1R,3S)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1S,3R)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)cyclopentanecarboxylicacid,(1RS,3S,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-fluorocyclopentanecarboxylicacid,(1RS,3RS,4RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-4-methoxycyclopentanecarboxylicacid,(1RS,3RS)-3-({[(1Z)-2-tert-butyl-2-methyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-1-methylcyclopentanecarboxylicacid, and(1RS,3SR)-3-({[(1Z)-2-tert-butyl-2-ethyl-1-oxido-1λ⁵-diazan-1-ylidene]amino}oxy)-1-methylcyclopentanecarboxylicacid, or a pharmaceutically acceptable salt thereof.
 33. Apharmaceutical composition comprising a compound of claim 19, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 34. A pharmaceutical composition comprising acompound of claim 32, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.
 35. A pharmaceutical compositioncomprising a compound of claim 19, or a pharmaceutically acceptable saltthereof, a diuretic, and a pharmaceutically acceptable carrier.
 36. Amethod for treating hypertension in a patient which comprisesadministering to the patient a therapeutically effective amount of thecomposition of claim 33.